The present invention relates to 2-phenyl-substituted imidazotriazinones, to processes for their preparation and to their use as pharmaceuticals, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
The published specification DE 28 11 780 describes imidazotriazines as bronchodilators having spasmolytic activity and inhibitory activity against phosphodiesterases which metabolize cyclic adenosin monophosphate (cAMP-PDEs, nomenclature according to Beavo: PDE-III and PDE-IV). An inhibitory action against phosphodiesterases which metabolize cyclic guanosin monophosphate (cGMP-PDEs, nomenclature according to Beavo and Reifsnyder (Trends in Pharmacol Sci 11, 150-155, 1990) PDE-I, PDE-II and PDE-V) has not been described. Compounds having a sulphonamide group in the aryl radical in the 2-position are not claimed. Furthermore, FR 22 13 058, CH 59 46 71, DE 22 55 172, DE 23 64 076 and EP 000 9384 describe imidazotriazinones which do not have a substituted aryl radical in the 2-position and are likewise said to be bronchodilators cAMP-PDE inhibitory action.
WO 94/28902 describes pyrazolopyrimidinones which are suitable for treating impotence.
The compounds according to the invention are potent inhibitors either of one or of more of the phosphodiesterases which metabolize cyclic guanosin 3xe2x80x2,5xe2x80x2-monophosphate (cGMP-PDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. II, 150-155, 1990) these are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.
An increase of the cGMP concentration can lead to beneficial antiaggregatory, antithrombotic, antiprolific, antivasospastic, vasodilative, natriuretic and diuretic effects. It can influence the short- or long-term modulation of vascular and cardiac inotropy, of the pulse and of cardiac conduction (J. C. Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).
The present invention, accordingly, provides 2-phenyl-substituted imidazotriazinones of the general formula (I) 
in which
R1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R2 represents straight-chain alkyl having up to 4 carbon atoms,
R3 and R4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 8 carbon atoms, or
xe2x80x83represents a straight-chain or branched alkyl chain having up to 10 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms and/or by radicals of the formulae xe2x80x94SO3H, xe2x80x94(A)axe2x80x94NR7R8, xe2x80x94Oxe2x80x94COxe2x80x94NR7xe2x80x2R8xe2x80x2, xe2x80x94S(O)bxe2x80x94R9, xe2x80x94P(O)(OR10)(OR11), 
xe2x80x83in which
a and b are identical or different and each represents a number 0 or 1,
A represents a radical CO or SO2,
R7, R7xe2x80x2, R8 and R8xe2x80x2 are identical or different and each represents hydrogen, or
xe2x80x83represents cycloalkyl having 3 to 8 carbon atoms; aryl having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated, optionally, benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula xe2x80x94(SO2)cxe2x80x94NR12R13, in which
c represents a number 0 or 1,
R12 and R13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or
R7, R7xe2x80x2, R8 and R8xe2x80x2 each represent straight-chain or branched alkoxy having up to 6 carbon atoms, or
xe2x80x83represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, halogen, aryl having 6 to 10 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula xe2x80x94(CO)dxe2x80x94NR14R15, in which
R14 and R15 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and
d represents a number 0 or 1, or
R7 and R8 and/or R7xe2x80x2 and R8xe2x80x2 together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula xe2x80x94NR16, in which
R16 represents hydrogen, aryl having 6 to 10 carbon atoms, benzyl, a 5- to 7-membered aromatic or saturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O which is optionally substituted by methyl, or
xe2x80x83represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl,
R9 represents aryl having 6 to 10 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms,
R10 and R11 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
xe2x80x83and/or the alkyl chain listed above under R3/R4 is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or by a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O or a radical of the formula xe2x80x94NR17, in which
R17 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 4 carbon atoms,
xe2x80x83or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 6 carbon atoms,
xe2x80x83and where aryl and the heterocycle are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of nitro, halogen, xe2x80x94SO3H, straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula xe2x80x94SO2xe2x80x94NR18R19, in which
R18 and R19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, and/or
R3 or R4 represents a group of the formula xe2x80x94NR20R21, in which
R20 and R21 have the meanings of R18 and R19 given above and are identical to or different from them, and/or
R3 or R4 represents adamantyl, or represents radicals of the formulae 
xe2x80x83or represents cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represents a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O, or a radical of the formula xe2x80x94NR22, in which
R22 has the meaning of R16 given above and is identical to or different from it, or represents carboxyl, formyl or straight-chain or branched acyl having up to 5 carbon atoms,
xe2x80x83and where cycloalkyl, aryl and/or the heterocycle are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of halogen, triazolyl, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and/or by groups of the formulae xe2x80x94SO3H, xe2x80x94OR23, (SO2)eNR24R25,xe2x80x94P(O)(OR26)(OR27), in which
e represents a number 0 or 1,
R23 represents a radical of the formula 
xe2x80x83represents cycloalkyl having 3 to 7 carbon atoms, or
xe2x80x83represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by cycloalkyl having 3 to 7 carbon atoms, benzyloxy, tetrahydropyranyl, tetrahydrofuranyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, carboxyl, benzyloxycarbonyl or phenyl which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl and halogen,
xe2x80x83and/or alkyl which is optionally substituted by radicals of the formulae xe2x80x94COxe2x80x94NR28R29 or xe2x80x94COxe2x80x94R30, in which
R28 and R29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or
R28 and R29 together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O, and
R30 represents phenyl or adamantyl,
R24 and R25 have the meanings of R18 and R19 given above and are identical to or different from them,
R26 and R27 have the meanings of R10 and R11 given above and are identical to or different from them
xe2x80x83and/or cycloalkyl, aryl and/or the heterocycle are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, carboxyl, by a 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, or by groups of the formula xe2x80x94SO2xe2x80x94R31, P(O)(OR32)(OR33) or xe2x80x94NR34R35, in which
R31 represents hydrogen or has the meaning of R9 given above and is identical to or different from it,
R32 and R33 have the meanings of R10 and R11 given above and are identical to or different from them,
R34 and R35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms, or
R34 and R35 together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may contain a further heteroatom from the group consisting of S and O, or a radical of the formula xe2x80x94NR36, in which
R36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl, or
R3 and R4 together with the nitrogen atom form a 5- to 7-membered unsaturated or saturated or partially unsaturated, optionally benzo-fused heterocycle which may optionally contain up to 3 heteroatoms from the group consisting of S, N and O, or a radical of the formula xe2x80x94NR37 in which
R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
xe2x80x83or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, or by groups of the formula xe2x80x94(D)fxe2x80x94NR38R39, xe2x80x94COxe2x80x94(CH2)gxe2x80x94Oxe2x80x94COxe2x80x94R40, xe2x80x94COxe2x80x94(CH2)hxe2x80x94OR41  or xe2x80x94P(O)(OR42)(OR43), in which
g and h are identical or different and each represents a number 1, 2, 3 or 4, and
f represents a number 0 or 1,
D represents a group of the formula xe2x80x94CO or xe2x80x94SO2,
R38 and R39 are identical or different and each has the meaning of R7 and R8 given above,
R40 represents straight-chain or branched alkyl having up to 6 carbon atoms,
R41 represents straight-chain or branched alkyl having up to 6 carbon atoms,
R42 and R43 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R37 represents a radical of the formula xe2x80x94(CO)ixe2x80x94E, in which
i represents a number 0 or 1,
E represents cycloalkyl having 3 to 7 carbon atoms or benzyl,
xe2x80x83represents aryl having 6 to 10 carbon atoms or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and O, where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different constituents selected from the group consisting of nitro, halogen, xe2x80x94SO3H, straight-chain or branched alkoxy having up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy, or by a radical of the formula xe2x80x94SO2xe2x80x94NR44R45, in which
R44 and R45 have the meanings of R18 and R19 given above and are identical to or different from them, or
E represents radicals of the formulae 
xe2x80x83and the heterocycle listed under R3 and R4, which is formed together with the nitrogen atom, is optionally mono- or polysubstituted, if appropriate also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro and groups of the formulae xe2x80x94P(O)(OR46)(OR47), 
xe2x80x83in which
R46 and R47 have the meanings of R10 and R11 given above and are identical to or different from them,
R48 represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms,
j represents a number 0 or 1, and
R49 and R50 are identical or different and have the meanings of R14 and R15 given above,
xe2x80x83and/or the heterocycle listed under R3 and R4, which is formed together with the nitrogen atom, is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cycloalkyl or cycloalkyloxy having in each case 3 to 8 carbon atoms, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, or by a radical of the formula xe2x80x94SO3H, xe2x80x94NR51R52 or P(O)OR53OR54, in which
R51 and R52 are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,
R53 and R54 are identical or different and have the meanings of R10 and R11 given above,
xe2x80x83and/or the alkyl is optionally substituted by aryl having 6 to 10 carbon atoms which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of halogen, hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms, or by a group of the formula xe2x80x94NR51xe2x80x2R52xe2x80x2, in which
R51xe2x80x2 and R52xe2x80x2 have the meanings of R51 and R52 given above and are identical to or different from them,
xe2x80x83and/or the heterocycle listed under R3 and R4, which is formed together with the nitrogen atom, is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, optionally also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, or
R3 and R4 together with the nitrogen atom form radicals of the formulae 
R5 and R6 are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or represents straight-chain or branched alkoxy having up to 6 carbon atoms,
and their salts, hydrates, N-oxides and isomeric forms.
The compounds according to the invention may exist in stereoisomeric forms which are related either as image and mirror image (enantiomers), or which are not related as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to their respective mixtures. The racemic forms can, just like the diastereomers, be separated in a known manner into the stereoisomerically pure constituents.
The substances according to the invention may also be present as salts. In the context of the invention, preference is given to physiologically acceptable salts.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
In the context of the invention, an optionally benzo-fused heterocycle generally represents a saturated, partially unsaturated or unsaturated 5- to 7-membered heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O. Examples which may be mentioned are: azepine, diazepine, indolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, thienyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, imidazolyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl or piperidinyl. Preference is given to quinolyl, furyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, piperazinyl, azepine, diazepine, thiazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.
In the context of the invention, a straight-chain or branched acyl radical having 1 to 6 carbon atoms represents, for example acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Preference is given to a straight-chain or branched acyl radical having 1 to 4 carbon atoms. Particular preference is given to acetyl and ethylcarbonyl.
In the context of the invention, a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preference is given to a straight-chain or branched alkoxy radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms. Particular preference is given to a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms.
In the context of the invention, a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms represents, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. Particular preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 3 carbon atoms.
In the context of the invention, a straight-chain or branched alkyl radical having 1 to 4, 1 to 6, 1 to 8 and 1-10 carbon atoms represents, for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Preference is given to straight-chain or branched alkyl radicals having 1 to 3, 1 to 4 or 1 to 8 carbon atoms. Particular preference is given to straight-chain or branched alkyl radicals having 1 to 4 or 1 to 3 carbon atoms.
In the context of the invention, straight-chain alkyl having up to 4 carbon atoms represents, for example, methyl, ethyl, n-propyl and n-butyl. (C6-C10)-Aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
In the context of the invention, cycloalkyl having 3 to 8 or 3 to 7 carbon atoms represents, for example, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Preference is given to: cyclopropyl, cyclopentyl and cyclohexyl.
In the context of the invention, cycloalkyloxy having 3 to 8 carbon atoms represents cyclopropyloxy, cyclopentyloxy, cyclobutyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy. Preference is given to: cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.
In the context of the invention, halogen generally represents fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine and bromine. Particular preference is given to fluorine and chlorine.
In the context of the invention and depending on the abovementioned substituents, a 5- to 6-membered or 7-membered saturated heterocycle, which may contain a further, heteroatom from the group consisting of S, N and O represents, for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or tetrahydrofuranyl. Preference is given to morpholinyl, tetrahydropyranyl, piperidinyl and piperazinyl.
In the context of the invention, a 5- to 6-membered aromatic heterocycle having up to 3 or 4 heteroatoms from the group consisting of S, O and N represents, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl.
In the context of the invention, a 5- to 6-membered unsaturated. partially unsaturated and saturated heterocycle which may contain up to 3 or 4 heteroatoms from the group consisting of S, O and N represents, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl or morpholinyl. Preference is given to pyridyl, pyrimidyl, piperazinyl, pyridazinyl, morpholinyl, furyl and thiazolyl.
The compounds according to the invention, in particular the salts, may also be present as hydrates. In the context of the invention, hydrates are those compounds which contain water in the crystal. Such compounds may contain one or more, typically 1 to 5, equivalents of water. Hydrates can be prepared, for example, by crystallizing the compound in question from water or from a water-containing solvent.
Preference is given to compounds of the general formula (I) according to the invention
in which
R1 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R2 represents straight-chain alkyl having up to 3 carbon atoms,
R3 and R4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 6 carbon atoms, or
xe2x80x83represents a straight-chain or branched alkyl chain having up to 8 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different constituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, and/or by radicals of the formulae xe2x80x94SO3H, xe2x80x94(A)axe2x80x94NR7R8, xe2x80x94Oxe2x80x94COxe2x80x94NR7xe2x80x2R8xe2x80x2, xe2x80x94S(O)bxe2x80x94R9, xe2x80x94P(O)(OR10)(OR11), 
xe2x80x83in which
a and b are identical or different and each represents a number 0 or 1,
R7, R7xe2x80x2, R8 and R8xe2x80x2 are identical or different and each represents hydrogen, or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, where the abovementioned ring systems are optionally mono- to trisubstituted by -identical or different substituents selected from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a group of the formula xe2x80x94(SO2)cxe2x80x94NR12R13, in which
c represents a number 0 or 1,
R12 and R13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R7, R7xe2x80x2, R8xe2x80x2 and R8xe2x80x2 each represent straight-chain or branched alkoxy having up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 7 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a group of the formula xe2x80x94(CO)dxe2x80x94NR14R15, in which
R14 and R15 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and
d represents a number 0 or 1, or
R7 and R8 and/or R7xe2x80x2 and R8xe2x80x2 together with the nitrogen atom form a pyrrolidinyl, morpholinyl, piperidinyl or triazolyl ring or radicals of the formulae 
xe2x80x83in which
R16 represents hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or represents straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl,
R9 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R10 and R11 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
xe2x80x83and/or the alkyl chain listed under R3/R4 is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, quinolyl, pyrrolidinyl, pyrimidyl, morpholinyl, furyl, piperidinyl, tetrahydrofuranyl or by radicals of the formulae 
xe2x80x83in which
R17 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 3 carbon atoms,
xe2x80x83or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 4 carbon atoms,
xe2x80x83and where phenyl and the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, xe2x80x94SO3H, straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, hydroxyl, and/or by a radical of the formula xe2x80x94SO2NR18R19, in which
R18 and R19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and/or
R3 or R4 represents a group of the formula xe2x80x94NR20R21, in which
R20 and R21 have the meanings of R18 and R19 given above and are identical to or different from them, and/or
R3 or R4 represents adamantyl, or represents radicals of the formulae 
xe2x80x83or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or represents radicals of the formulae 
xe2x80x83in which
R22 has the meaning of R16 given above and is identical to or different from it, or
xe2x80x83represents carboxyl, formyl or straight-chain or branched acyl having up to 3 carbon atoms,
xe2x80x83and where cycloalkyl, phenyl and/or the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, triazolyl, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro and/or by groups of the formulae xe2x80x94SO3H, xe2x80x94OR23, (SO2)eNR24R25, xe2x80x94P(O)(OR26)(OR27), in which
e represents a number 0 or 1,
R23 represents a radical of the formula 
xe2x80x83represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl or cycloheptyl,
xe2x80x83represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which may optionally be substituted by cyclopropyl, cyclopentyl, cyclohexyl, benzyloxy, tetrahydropyranyl, tetrahydrofuranyl, straight-chain or, branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, benzyloxycarbonyl or phenyl which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl, fluorine and chlorine,
xe2x80x83and/or where alkyl is optionally substituted by radicals of the formulae xe2x80x94COxe2x80x94NR28R29 or xe2x80x94COxe2x80x94R30, in which
R28 and R29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or
R28 and R29 together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring, and
R30 represents phenyl or adamantyl,
R24 and R25 have the meanings of R18 and R19 given above and are identical to or different from them,
R26 and R27 have the meanings of R10 and R11 given above and are identical to or different from them
xe2x80x83and/or cycloalkyl, phenyl and/or the heterocycles are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or by groups of the formula xe2x80x94SO2xe2x80x94R31, xe2x80x94P(O)(OR32)(OR33) or xe2x80x94NR34R35, in which
R31 has the meaning of R9 given above and is identical to or different from it,
R32 and R33 have the meanings of R10 and R11 given above and are identical to or different from them,
R34 and R35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms, or
R34 and R35 together with the nitrogen atom form a morpholinyl triazolyl or thiomorpholinyl ring or a radical of the formula 
xe2x80x83in which
R36 represents hydrogen, hydroxyl, straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by hydroxyl, or
R3 and R4 together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring, or a radical of the formula 
xe2x80x83in which
R37 represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms,
xe2x80x83or represents straight-chain or branched alkyl having up to 5 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by groups of the formula xe2x80x94(D)fxe2x80x94NR38R39, xe2x80x94COxe2x80x94(CH2)gxe2x80x94Oxe2x80x94COxe2x80x94R40xe2x80x94COxe2x80x94(CH2)hxe2x80x94OR41 or xe2x80x94P(O)(OR42)(OR43), in which
g and h are identical or different and each represents a number 1, 2 or 3, and
f represents a number 0 or 1,
D represents a group of the formula xe2x80x94CO or xe2x80x94SO2,
R38 and R39 are identical or different and have the meanings of R7 and R8 given above,
R40 represents straight-chain or branched alkyl having up to 4 carbon atoms,
R41 represents straight-chain or branched alkyl having up to 4 carbon atoms,
R42 and R43 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
R37 represents a radical of the formula xe2x80x94(CO)ixe2x80x94E, in which
i represents a number 0 or 1,
E represents cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, where the abovementioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, xe2x80x94SO3H, straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy or by a radical of the formula xe2x80x94SO2xe2x80x94NR44R45, in which
R44 and R45 have the meanings of R18 and R19 given above and are identical to or different from them, or
E represents radicals of the formulae 
xe2x80x83and the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro and groups of the formulae xe2x80x94P(O)(OR46)(OR47), 
xe2x80x83in which
R46 and R47 have the meanings of R10 and R11 given above and are identical to or different from them,
R48 represents hydroxyl or straight-chain or branched alkoxy having up to 3 carbon atoms,
j represents a number 0 or 1, and
R49 and R50 are identical or different and have the meanings of R14 and R15 given above,
xe2x80x83and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by straight-chain or branched alkyl having up to 5 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, or by a radical of the formula xe2x80x94SO3H, xe2x80x94NR51R52 or xe2x80x94P(O)OR53OR54, in which
R51 and R52 are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,
R53 and R54 are identical or different and have the meanings of R10 and R11 given above,
xe2x80x83and/or the alkyl is optionally substituted by phenyl which for its part may be mono- to trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms, or by a group of the formula xe2x80x94NR51R52xe2x80x2, in which
R51xe2x80x2 and R52xe2x80x2 have the meanings of R51 and R52 given above and are identical to or different from them,
xe2x80x83and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, optionally also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or
R3 and R4 together with the nitrogen atom form radicals of the formulae 
R5 and R6 are identical or different and each represents hydrogen, hydroxyl or represents straight-chain or branched alkoxy having up to 4 carbon atoms,
and their salts, N-oxides, hydrates and isomeric forms.
Particular preference is given to compounds of the general formula (I) according to the invention
in which
R1 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R2 represents straight-chain alkyl having up to 3 carbon atoms,
R3 and R4 are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 4 carbon atoms, or
xe2x80x83represents a straight-chain or branched alkyl chain having up to 6 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, and/or by radicals of the formulae xe2x80x94SO3H, xe2x80x94(A)axe2x80x94NR7R8, xe2x80x94Oxe2x80x94COxe2x80x94NR7xe2x80x2R8xe2x80x2, xe2x80x94S(O)bxe2x80x94R9, xe2x80x94P(O)(OR10)(OR11), 
xe2x80x83in which
a and b are identical or different and each represents a number 0 or 1,
A represents a radical CO or SO2,
R7, R7xe2x80x2, R8 and R8 xe2x80x2 are identical or different and, each represents hydrogen, or
xe2x80x83represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl and pyridyl, where the abovementioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, carboxyl, fluorine, chlorine, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a group of the formula xe2x80x94(SO2)cxe2x80x94NR12R13, in which
c represents a number 0 or 1,
R12 and R13 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or
R7, R7xe2x80x2, R8 and R8xe2x80x2 each represent methoxy, or
xe2x80x83represent straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, phenyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a group of the formula xe2x80x94(CO)dxe2x80x94NR14R15, in which
R14 and R15 are identical or different and each represents hydrogen, methyl or ethyl, and
d represents a number 0 or 1, or
R7 and R8 and/or R7xe2x80x2 and R8xe2x80x2 together with the nitrogen atom form a morpholinyl, piperidinyl or triazolyl ring or radicals of the formulae 
xe2x80x83in which
R16 represents hydrogen, phenyl, benzyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or N-methylpiperazinyl, or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl,
R9 represents methyl,
R10 and R11 are identical or different and each represents hydrogen, methyl or ethyl,
xe2x80x83and/or the alkyl chain listed under R3/R4 is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl, or by radicals of the formulae 
xe2x80x83in which
R17 represents hydrogen, hydroxyl, formyl, acetyl or alkoxy having up to 3 carbon atoms,
xe2x80x83or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 3 carbon atoms,
xe2x80x83and where phenyl and the heterocycles are optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, xe2x80x94SO3H, straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, hydroxyl, and/or by a radical of the formula xe2x80x94SO2NR18R19, in which
R18 and R19 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and/or
R3 or R4 represents a group of the formula xe2x80x94NR20R21, in which
R20 and R21 have the meanings of R18 and R19 given above and are identical to or different from them, and/or
R3 or R4 represents adamantyl, or represents radicals of the formulae 
xe2x80x83or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl, morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or represents radicals of the formulae 
xe2x80x83in which
R22 has the meaning of R16 given above and is identical to or different from it, or represents formyl or acetyl,
xe2x80x83and where cycloalkyl, phenyl and/or the heterocycles are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, triazolyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, and/or by groups of the formulae xe2x80x94SO3H, xe2x80x94OR23, (SO2)eNR24R25,xe2x80x94P(O)(OR26)(OR27), in which
e represents a number 0 or 1,
R23 represents a radical of the formula 
xe2x80x83represents cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl,
xe2x80x83represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by cyclopropyl, cyclohexyl, benzyloxy, tetrahydropyranyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, benzyloxycarbonyl or phenyl which for its part may be mono- or disubstituted by identical or different substituents selected from the group consisting of methoxy, hydroxyl, fluorine or chlorine,
xe2x80x83and/or where alkyl is optionally substituted by radicals of the formulae xe2x80x94COxe2x80x94NR28R29 or xe2x80x94COxe2x80x94R30, in which
R28 and R29 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R28 and R29 together with the nitrogen atom form a morpholinyl, pyrrolidinyl or piperidinyl ring, and
R30 represents phenyl or adamantyl,
R24 and R25 have the meanings of R18 and R19 given above and are identical to or different from them,
R26 and R27 have the meanings of R10 and R11 given above and are identical to or different from them
xe2x80x83and/or cycloalkyl, phenyl and/or the heterocycles are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, triazolyl or by groups of the formula xe2x80x94SO2xe2x80x94R31, P(O)(OR32)(OR33) or xe2x80x94NR34R35, in which
R31 represents methyl,
R32 and R33 have the meanings of R10 and R11 given above and are identical to or different from them,
R34 and R35 are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl or methoxy, or
R34 and R35 together with the nitrogen atom form a morpholinyl, triazolyl or thiomorpholinyl ring, or a radical of the formula 
xe2x80x83in which
R36 represents hydrogen, hydroxyl, straight chain or branched alkoxycarbonyl having up to 3 carbon atoms or straight-chain or branched alkyl having up to 3 carbon atoms which is optionally substituted by hydroxyl, or
R3 and R4 together with the nitrogen atom form a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl ring, or a radical of the formula 
xe2x80x83in which
R37 represents hydrogen, hydroxyl, formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms,
xe2x80x83or represents straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by groups of the formula xe2x80x94(D)fxe2x80x94NR38R39, xe2x80x94COxe2x80x94(CH2)gxe2x80x94Oxe2x80x94COxe2x80x94R40, xe2x80x94COxe2x80x94(CH2)hxe2x80x94OR41 or xe2x80x94P(O)(OR42)(OR43), in which
g and h are identical or different and each represents a number 1 or 2, and
f represents a number 0 or 1,
D represents a group of the formula xe2x80x94CO or xe2x80x94SO2,
R38 and R39 are identical or different and have the meanings of R7 and R8 given above,
R40 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R41 represents straight-chain or branched alkyl having up to 3 carbon atoms,
R42 and R43 are identical or different and each represents hydrogen, methyl or ethyl, or
R37 represents a radical of the formula xe2x80x94(CO)ixe2x80x94E, in which
i represents a number 0 or 1,
E represents cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl or furyl, where the abovementioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of nitro, fluorine, chlorine, xe2x80x94SO3H, straight-chain or branched alkoxy having up to 3 carbon atoms, hydroxyl, or by a radical of the formula xe2x80x94SO2xe2x80x94NR44R45, in which
R44 and R45 have the meanings of R18 and R19 given above and are identical to or different from them, or
E represents radicals of the formulae 
xe2x80x83and the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally mono- to trisubstituted, optionally also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, or groups of the formulae xe2x80x94P(O)(OR46)(OR47), 
xe2x80x83in which
R46 and R47 have the meanings of R10 and R11 given above and are identical to or different from them,
R48 represents hydroxyl or methoxy,
j represents a number 0 or 1, and
R49 and R50 are identical or different and have the meanings of R14 and R15 given above,
xe2x80x83and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents selected from the group consisting of hydroxyl, fluorine, chlorine, carboxyl, cyclopropyl, cycloheptyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by a radical of the formula xe2x80x94SO3H, xe2x80x94NR51R52 or P(O)OR53OR54, in which
R51 and R52 are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms,
R53 and R54 are identical or different and have the meanings of R10 and R11 given above,
xe2x80x83and/or the alkyl is optionally substituted by phenyl which for its part may be mono- to disubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, hydroxyl, methoxy, or by a group of the formula xe2x80x94NR51xe2x80x2R52xe2x80x2, in which
R51xe2x80x2 and R52xe2x80x2 have the meanings of R51 and R52 given above and are identical to or different from them,
xe2x80x83and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or tetrazolyl, if appropriate also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, or
R3 and R4 together with the nitrogen atom form radicals of the formulae 
R5 and R6 are identical or different and each represents hydrogen, hydroxyl or represents straight-chain or branched alkoxy having up to 3 carbon atoms,
and their salts, N-oxides, hydrates and isomeric forms.
Very particular preference is given to compounds of the general formula (I),
in which
R1 represents methyl or ethyl,
R2 represents ethyl or propyl,
R3 and R4 are identical or different and each represents a straight-chain or branched alkyl chain having up to 5 carbon atoms which is optionally substituted up to two times by identical or different substituents selected from the group consisting of hydroxyl and methoxy, or
R3 and R4 together with the nitrogen atom form a piperidinyl, morpholinyl, thiomorpholinyl ring, or a radical of the formula 
xe2x80x83in which
R37 represents hydrogen, formyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms,
xe2x80x83or represents straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, or by groups of the formulae xe2x80x94(D)fxe2x80x94NR38R39 or xe2x80x94P(O)(OR42)(OR43), in which
f represents a number 0 or 1,
D represents a group of the formula xe2x80x94CO,
R38 and R39 are identical or different and each represents hydrogen or methyl,
R42 and R43 are identical or different and each represents hydrogen, methyl or ethyl, or
R37 represents cyclopentyl,
xe2x80x83and the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally mono- or disubstituted, optionally also geminally, by identical or different; substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 3 carbon atoms, or groups of the formulae xe2x80x94P(O)(OR46)(OR47) or xe2x80x94(CO)iNR49R50, in which
R46 and R47 are identical or different and each represents hydrogen, methyl or ethyl,
j represents a number 0 or 1, and
R49 and R50 are identical or different and each represents hydrogen or methyl
xe2x80x83and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by straight-chain or branched alkyl having up to 3 carbon atoms which is optionally mono- or disubstituted by identical or different substituents selected from the group consisting of hydroxyl, carboxyl, or by a radical of the formula P(O)OR53R54, in which
R53 and R54 are identical or different and each represents hydrogen, methyl or ethyl,
xe2x80x83and/or the heterocycles listed under R3 and R4, which are formed together with the nitrogen atom, are optionally substituted by pyrrolidinyl or piperidinyl attached via nitrogen,
R5 represents hydrogen, and
R6 represents ethoxy or propoxy,
and their salts, hydrates, N-oxides and isomeric forms.
Likewise, very particular preference is given to those compounds of the general formula (I) according to the invention in which R5 represents hydrogen and the radicals R6 and xe2x80x94SO2NR3R4 are in a position para to one another at the phenyl ring.
Particularly preferred compounds are listed in Table A.
The invention furthermore provides a process for preparing the compounds of the general formula (I) according to the invention, characterized in that
initially compounds of the general formula (II) 
xe2x80x83in which
R1 and R2 are each as defined above and
L represents straight-chain or branched alkyl having up to 4 carbon atoms,
are converted with compounds of the general formula (III) 
xe2x80x83in which
R5 and R6 are each as defined above,
in a two-step reaction in the systems ethanol and phosphorus oxytrichloride/dichloroethane into the compounds of the general formula (IV) 
xe2x80x83in which
R1, R2, R5 and R6 are each as defined above,
which are reacted in a further step with chlorosulphonic acid to give the compounds of the general formula (V) 
xe2x80x83in which
R1, R2, R5 and R6 are each as defined above,
which are finally reacted with amines of the general formula (VI)
HN3R4xe2x80x83xe2x80x83(VI)
xe2x80x83in which
R3 and R4 are each as defined above,
in inert solvents.
The process according to the invention can be illustrated using the following scheme as an example: 
Solvents which are suitable for the individual steps are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the abovementioned solvents. Particular preference is given to ethanol for the first step and dichloroethane for the second step.
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out in a range of from xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably of from 0xc2x0 C. to 70xc2x0 C.
The process steps according to the invention are generally carried out under atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example, in a range of from 0.5 to 5 bar).
The reaction to give the compounds of the general formula (V) is carried out in a temperature range of from 0xc2x0 C. to room temperature, and at atmospheric pressure.
The reaction with the amines of the general formula (VI) is carried out in one of the abovementioned chlorinated halogens, preferably in dichloromethane.
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out at temperatures in a range of from xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably of from 0xc2x0 C. to room temperature.
The reaction is generally carried out at atmospheric pressure. However, it is also possible to operate under superatmospheric pressure or under reduced pressure (for example in a range of from 0.5 to 5 bar).
Some of the compounds of the general formula (II) are known, or they are novel, and they can then be prepared by
converting compounds of the general formula (VII)
R2xe2x80x94COxe2x80x94Txe2x80x83xe2x80x83(VII)
xe2x80x83in which
R2 is as defined above and
T represents halogen, preferably chlorine,
initially by reaction with compounds of the general formula (VIII) 
xe2x80x83in which
R1 is as defined above
in inert solvents, if appropriate in the presence of a base and trimethylsilyl chloride, into the compounds of the general formula (IX) 
xe2x80x83in which
R1 and R2 are each as defined above,
and finally reacting with the compound of the formula (X) 
xe2x80x83in which
L is as defined above,
in inert solvents, if appropriate in the presence of a base.
Suitable solvents for the individual steps of the process are the customary organic solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is also possible to use mixtures of the abovementioned solvents. Particular preference is given to dichloromethane for the first step and to a mixture of tetrahydrofuran and pyridine for the second step.
Suitable bases are generally alkali metal hydrides or alkali metal alkoxides, such as, for example, sodium hydride or potassium tert-butoxide, or cyclic amines, such as, for example, piperidine, pyridine, dimethylaminopyridine or C1-C4 alkylamines, such as, for example, triethylamine. Preference is given to triethylamine, pyridine and/or dimethylaminopyridine.
The base is generally employed in an amount of from 1 mol to 4 mol, preferably from 1.2 mol to 3 mol, in each case based on 1 mol of the compound of the formula (X).
The reaction temperature can generally be varied within a relatively wide range. In general, the reaction is carried out in a range of from xe2x88x9220xc2x0 C. to 200xc2x0 C., preferably of from 0xc2x0 C. to 100xc2x0 C.
The compounds of the general formulae (VII), (VIII), (IX) and (X) are known per se, or they can be prepared by customary methods.
The compounds of the general formula (III) can be prepared by
reacting compounds of the general formula (XI) 
xe2x80x83in which
R5 and R6 are each as defined above with ammonium chloride in toluene and in the presence of trimethylaluminium in hexane in a temperature range of from xe2x88x9220xc2x0 C. to room temperature, preferably at, 0xc2x0 C. and atmospheric pressure, and reacting the resulting amidine, if appropriate in situ, with hydrazine hydrate.
The compounds of the general formula (XI) are known per se, or they can be prepared by customary methods.
Some of the compounds of the general formula (IV) are known, or they are novel, in which case they can be prepared by known methods [cf. David R. Marshall, Chemistry and Industry, May 2, 1983, 331-335].
Compounds of the general formula (V) are novel per se, however, they can be prepared from the compounds of the general formula (IV) in accordance with the publication Organikum, VEB Deutscher Verlag der Wissenschaften, Berlin 1974, pages 338-339.
The compounds of the general formula (I) according to the invention have an unforeseeable useful pharmacological activity spectrum.
They inhibit either one or more of the cGMP-metabolizing phosphodiesterases(PDE I, PDE II and PDE V). This results in an increase of cGMP. The differentiated expression of the phosphodiesterases in different cells, tissues and organs, as well as the differentiated subcellular localization of these enzymes, in combination with the selective inhibitors according to the invention make it possible to selectively address the various cGMP-regulated processes.
Moreover, the compounds according to the invention enhance the activity of substances such as, for example EDRF (endothelium derived relaxing factor), ANP (atrial natriuretic peptide), of nitrovasodilators and all other substances which increase the cGMP concentration in a manner different from that of phophodiesterase inhibitors.
They can therefore be employed in pharmaceuticals for treating cardiovascular disorders, such as, for example, for treating hypertension, neuronal hyertonia, stable and unstable angina, peripheral and cardial vascularpathies, arrhythmiae, for treating thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transistory and ischaemic attacks, angina pectoris, obstruction of peripheral circulation, prevention of restenoses after thrombolysis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasties (PTCA) and bypass. Furthermore, they may also be of significance for cerebrovascular disorders. Owing to their relaxing action on smooth muscles, they are suitable for treating disorders of the urogenital system such as hypertrophy of the prostate, incontinence and in particular for treating erectile dysfunction and female sexual dysfunction.
Activity of the Phosphodiesterases (PDEs)
The cGMP-stimulated PDE II, the cGMP-inhibited PDE III and the cAMP-specific PDE IV were isolated either from porcine or bovine heart myocardium. The Ca2+-calmodulin-stimulated PDE I was isolated from porcine aorta, porcine brain or, preferably, from bovine aorta. The cGMP-specific PDE V was obtained from porcine small intestine, porcine aorta, human platelets and, preferably, from bovine aorta. Purification was carried out by anion exchange chromatography over MonoQ(copyright) Pharmacia, essentially following the method of M. Hoey and Miles D. Houslay, Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Luginan et al., Biochemical Pharmacology, Vol. 35, 1743-1751 (1986).
The enzyme activity is determined using a test mixture of 100 ml in 20 mM tris/HCl-buffer pH 7.5 containing 5 mM MgCl2, 0.1 mg/ml of bovine serum albumin and either 800 Bq[3H]cAMP or [3H]cGMP. The final concentration of the nucleotides in question is 10xe2x88x926 mol/l. The reaction is initiated by addition of the enzyme and the amount of enzyme is such that during the incubation time of 30 min, approximately 50% of the substrate are converted. To test the cGMP-stimulated PDE II, [3H]cAMP is used as substrate and 10xe2x88x926 mol/l of non-labelled cGMP are added to the mixture. To test the Ca2+-amodulin-dependent PDE I, 1 mM of CaCl2 and 0.1 mM of calmodulin are added to the reaction mixture. The reaction is quenched by addition of 100 ml of acetonitrile containing 1 mM cAMP and 1 mM AMP. 100 ml of the reaction mixture are separated by HPLC, and the cleavage products are determined quantitatively on-line using a continuous scintillation counter. The substance concentration measured is the concentration at which the reaction rate is reduced by 50%. Additionally, the xe2x80x9cphosphodiesterase [3H] cAMP-SPA enzyme assayxe2x80x9d and the xe2x80x9cphosphodiesterase [3H] cGMP-SPA enzyme assayxe2x80x9d from Amersham Life Science were used for testing. The test was carried out according to the test protocol of the manufacturer. To determine the activity of PDE II, the [3H]cAMP SPA assay was used, and 10xe2x88x926 M cGMP were added to the reaction mixture to activate the enzyme. To measure PDE I, 10xe2x88x927 M calmodulin and 1 mM CaCl2 were added to the reaction mixture. PDE V was measured using the [3H]cGMP SPA assay.
In principle, inhibition of one or more phosphodiesterases of this type results in an increase of the cGMP concentration. Thus, the compounds are of interest for all therapies in which an increase of the cGMP concentration is considered to be beneficial.
The cardiovascular effects were investigated using SH-rats and dogs. The substances were administered intravenously or orally.
The erection-stimulating action was investigated using rabbits which were awake [Naganuma H, Egashira T, Fuji J, Clinical and Experimental Pharmacology and Physiology 20, 177-183 (1993)]. The substances were administered intravenously, orally or parenterally.
The novel active compounds and their physiologically acceptable salts (for example hydrochlorides, maleates or lactates) can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert non-toxic, pharmaceutically suitable excipients or solvents. In this case the therapeutically active compound should in each case be present in a concentration from approximately 0.5 to 90% by weight of the total mixture, i.e. in amounts which are sufficient in order to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the active compounds using solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, it optionally being possible, for example, to use organic solvents as auxiliary solvents if the diluent used is water.
Administration is carried out in a customary manner, preferably orally, transdermally or parenterally, for example perlingually, buccally, intravenously, nasally, rectally or inhalatively.
For human use, in the case of oral administration, it is good practice to administer doses of from 0.001 to 50 mg/kg, preferably of 0.01 mg/kg-20 mg/kg. In the case of parenteral administration, such as, for example, via mucous membranes nasally, buccally or inhalatively, it is good practice to use doses of 0.001 mg/kg-0.5 mg/kg.
In spite of this, if appropriate it may be necessary to depart from the amounts mentioned, namely depending on the body weight or the type of administration route, on the individual response towards the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amounts, while in other cases the upper limit mentioned has to be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide these into several individual doses over the course of the day.
The compounds according to the invention are also suitable for use in veterinary medicine. For use in veterinary medicine, the compounds or their non-toxic salts can be administered in a suitable formulation in accordance with general veterinary practice. Depending on the kind of animal to be treated, the veterinary surgeon can determine the nature of use and the dosage.

22.27 g (250 mmol) of D,L-alanine and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0xc2x0 C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and for 1 hour at 40xc2x0 C. After cooling to xe2x88x9210xc2x0 C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred for 2 hours at xe2x88x9210xc2x0 C. and for one hour at room temperature.
With ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous phase is evaporated to dryness, the residue is titrated with acetone and the mother. liquor is filtered off with suction. The solvent is removed and the residue is chromatographed. The resulting product is dissolved in 3N aqueous sodium hydroxide solution and the resulting solution is evaporated to dryness. The residue is taken up in conc. HCl and once more evaporated to dryness. The residue is stirred with acetone, precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. This gives 28.2 g (71%) of a viscous oil which crystallizes after some time.
200 MHz 1H-NMR (DMSO-d6): 0.84, t, 3H; 1.22, d, 3H; 1.50, hex, 2H; 2.07, t, 2H; 4.20, quin., 1H; 8.09, d, 1H.

25.78 g of 2-aminobutyric acid (250 mmol) and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0xc2x0 C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and for 1 hour at 40xc2x0 C. After cooling to xe2x88x9210xc2x0 C., 26.64 g (250 mmol) of butyrylchloride are added dropwise,and the resulting mixture is stirred for 2 hours at xe2x88x9210xc2x0 C. and for one hour at room temperature.
With ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The organic phase is admixed with aqueous sodium hydroxide solution and the organic solvent is removed under reduced pressure. After acidification, the precipitated solid is stirred once with water and twice with petroleum ether and dried at 45xc2x0 C. under reduced pressure. This gives 29.1 g (67%) of a colourless solid.
200 MHz 1H-NMR (DMSO-d6):0.88, 2t, 6H; 1.51, quart., 2H, 1.65, m, 2H, 2.09, t, 2H, 4.10, m, 1H; 8.01, d, 1H; 12.25, s, m 1H.

25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 30.0 g (97%) of a colourless liquid.
200 MHz 1H-NMR (DMSO-d6): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H; 7.51, dt, 2H.

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene, and the suspension is cooled to 0xc2x0 C. 200 ml of a 2M solution of trimethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reaction mixture is stirred at 80xc2x0 C. (bath) overnight.
With ice-cooling, the cooled reaction mixture is added to a suspension of 100 g of silica gel and 950 ml of chloroform, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered off with suction, and the filter residue is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is stirred with a mixture of dichloromethane and methanol (9:1), the solid is filtered off with suction and the mother liquor is concentrated. This gives 30.4 g (76%) of a colourless solid.
200 MHz 1H-NMR (DMSO-d6): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, 1H; 7.21, d, 1H; 7.52, m, 2H; 9.30, s, broad, 4H.

75 g (630 ml) of 2-hydroxybenzonitrile are refluxed with 174 g (1.26 mol) of potassium carbonate and 232.2 g (1.89 mol) of ethyl bromide in 11 of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure.
b.p.: 89xc2x0 C. (0.7 mbar)
Yield: 95.1 g (93.7%)

21.41 g (400 mmol) of ammonium chloride are suspended in 400 ml of toluene and cooled to 0-5xc2x0 C. 200 ml of a 2M solution of triethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 32.2 g (200 mmol) of 2-propoxybenzonitrile, the reaction mixture is stirred at 80xc2x0 C. (bath) overnight. With ice-cooling, the cooled reaction mixture is added to a suspension of 300 g of silica gel and 2.85 of ice-cooled chloroform, and the mixture is stirred for 30 minutes. The mixture is filtered off with suction and the filter residue is washed with the same amount of methanol. The solvent is distilled off under reduced pressure, the residue is stirred with 500 ml of a mixture of dichloromethane and methanol (9:1), the solid is filtered off and the mother liquor is concentrated. The residue is stirred with petroleum ether and filtered off with suction. This gives 22.3 g (52%) of product.
1H-NMR (200 MHz, CD3OD): 1.05 (3H); 1.85 (sex, 2H); 4.1 (A, 2H); 7.0-7.2 (m, 2H); 7.5-7.65 (m, 2H).

30.0 g (201 mmol) of 2-hydroxy-4-methoxybenzonitrile are refluxed with 83.4 g of potassium carbonate (603 mmol) and 32.88 g (301 mmol) of bromoethane in 550 ml of acetone for 18 hours. After filtration, the solvent is removed under reduced pressure and the residue is purified by silica gel chromatography (cyclohexane:ethyl acetate=10:1): 35.9 g of an oil Rf=0.37 (cyclohexane:ethyl acetate=3:1)
200 MHz 1H-NMR (CDCl3): 1.48, t, 3H; 3.85, s, 3H; 4.12, quart., 2H; 6.46, m, 2H 7.48, d, 1H.

6.98 g (130 mmol) of ammonium chloride are suspended in 150 ml of toluene, and the suspension is cooled to 0xc2x0 C. 70 ml of a 2M solution of trimethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 11.56 g (65 mmol) of 2-ethoxy-4-methoxybenzonitrile, the reaction mixture is stirred at 80xc2x0 C. (bath) overnight.
With ice-cooling, the cooled reaction mixture is added to a suspension of 100 g of silica gel and 950 ml of dichloromethane, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered off with suction and the filter residue is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is stirred with a mixture of dichloromethane and methanol (9:1), the solid is filtered off with suction and the mother liquor is concentrated. The residue is stirred with petroleum ether and filtered off with suction. This gives 7.95 g (50%) of a solid.
200 MHz 1H-NMR (DMSO-d6): 1.36, t, 3H; 3.84, s, 3H; 4.15, quart., 2H; 6.71, m, 2H; 7.53, d, 1H, 8.91, s, broad, 3H.

24.4 g (0.186 mol) of N-acetyl-D,L-alanine are initially charged in 200 ml of absolute tetrahydrofuran, and 45 ml of absolute pyridine and 0.5 g of 4-dimethylaminopyridine are added. The mixture is heated to reflux, and 51.85 g (0.372 mol) of ethyl oxalyl chloride are added dropwise. The mixture is heated under reflux for a further 90 minutes, cooled, poured into ice-water and extracted three times, with ethyl acetate. The organic phase is dried over sodium sulphate, concentrated and taken up in 62.5 ml of methanol. 9 g of sodium bicarbonate are added and the mixture is stirred under reflux for 2.5 hours and filtered.
With ice-cooling, 9.54 g (190.65 mmol) of hydrazine hydrate are added dropwise to a solution of 38.26 g (190.65 mmol) of 2-ethoxy-4-methoxybenzamidine hydrochloride in 250 ml of methanol, and the resulting suspension is stirred at room temperature for another 30 minutes. The methanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70xc2x0 C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.
The residue is taken up in 250 ml of 1,2-dichloroethane, 32.1 ml (348 mmol) of phosphorus oxychloride are added dropwise and the mixture is heated under reflux for two hours. The mixture is cooled, concentrated, taken up in a little methylene chloride and admixed with diethyl ether, and the solid is filtered off with suction. After the silica gel chromatography (methylene chloride/methanol 95:5), the solution is concentrated and the crystalline residue is stirred with diethyl ether.
Yield: 8.1 g (14.9% of theory)
200 MHz 1H-NMR (CDCl3): 1.58, t, 3H; 2.62, s, 3H; 2.68, s, 3H; 4.25, q, 2H; 7.04, d, 1H; 7.12, t, 1H; 7.5, dt, 1H; 8.19, dd, 1H; 10.02, s, 1H.

7.16 g (45 mmol) of 2-butyrylamino-propionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF and, after addition of a spatula tip of DMAP, heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.
With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are added dropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The ethanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70xc2x0 C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.
This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography using ethyl acetate and crystallization afford 4.00 g (28%) of a colourless solid, Rf=0.42 (dichloromethane/methanol=95:5)
200 MHz 1H-NMR (CDCl3): 1.02, t, 3H; 1.56, t, 3H; 1.89, hex, 2H; 2.67, s, 3H; 300, t, 2H; 4.26, quart., 2H; 7.05, m, 2H; 7.50, dt, 1H; 8.17, dd, 1H; 10.00, s, 1H.

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridine are dissolved in 45 ml of tetrahydrofuran and, after addition of a spatula tip of dimethylaminopyridine, heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.
With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are added dropwise to a solution of 9.66 g (45 mmol) of 2-propoxybenzamidine hydrochloride in 45 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The ethanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70xc2x0 C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is reduced under reduced pressure.
This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Crystallization from ethyl acetate gives 2.85 g (19.1%) of a yellow solid, chromatographic purification of the mother liquor gives a further 1.25 g (8.4%) of the product. Rf=0.45 (dichloromethane/methanol=95:5)
200 MHz 1H-NMR (CDCl3): 1.03, t, 3H; 1.15, t, 3H; 1.92, m, 4H; 2.67, s, 3H; 3.01, t, 2H; 4.17, t., 2H; 7.09, m, 2H; 7.50, dt, 1H; 8.17, dd, 1H; 10.02, s, 1H.

5.50 g (34.8 mmol) of 2-butyrylaminopropionic acid and 8.190 g of pyridine are dissolved in 35 ml of tetrahydrofuran and, after addition of a spatula tip of dimethylaminopyridine, heated to reflux. 9.43 g (69 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 11 ml of methanol and refluxed with 1.65 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.
With ice-cooling, 1.73 g (34.5 mmol) of hydrazine hydrate are added dropwise to a solution of 7.95 g (34.5 mmol) of 2-ethoxy-4-methoxybenzamidine hydrochloride in 35 ml of ethanol, and the resulting suspension is stirred at room temperature for another 30 minutes. The methanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70xc2x0 C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.
This residue is dissolved in 46 ml of 1,2-dichloroethane and, after addition of 5.74 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography (dichloromethane:methanol=50:1) gives 0.31 g (2.5%) of a solid. Rf=0.46 (dichloromethane:methanol=20:1)
200 MHz 1H-NMR (CDCl3): 1.03, t, 3H; 1.58, t, 3H; 1.88, m, 2H; 2.62, s, 3H; 2.98, t, 2H; 3.89, s, 3H; 4.25, quart., 2H; 6.54, d, 1H, 6.67, dd, 1H; 8.14, d, 1H; 9.54, s, 1H.

29.06 g (167.8 mmol) of 2-butyrylaminobutyric acid and 39.76 g of pyridine are dissolved in 170 ml of tetrahydrofuran and, after addition of a spatula tip of dimethylaminopyridine, heated to reflux. 45.81 g (335.5 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of methanol, and half of the solution is refluxed with 7.96 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.
With ice-cooling, 4.20 g (83.9 mmol) of hydrazine hydrate are added dropwise to a solution of 16.83 g (83.9 mmol) of 2-ethoxybenzamidine hydrochloride in 85 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The methanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70xc2x0 C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.
This residue is dissolved in 112 ml of 1,2-dichloroethane and, after addition of 14 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography (dichloromethane:methanol=50:1) lives 3.69 g (12.4%) of a colourless solid, Rf=0.46 (dichloromethane:methanol=20:1)
200 MHz 1H-NMR (CDCl3): 1.32, t, 3H; 1.57, t, 3H; 1.94, m, 8H; 3.03, quart., 2H; 3.64, quin., 1H; 4.27, quart., 2H; 7.06, d, 1H; 7.12, t, 1H; 7.50, dt, 1H, 8.16, dd, 1H; 9.91, s, 1H.

7.25 g (25.5 mmol) of 2-(2-ethoxyphenyl)-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are initially charged, and 26.74 g (0.23 mol) of chlorosulphonic acid are added with ice-cooling,. The mixture is stirred at room temperature overnight and poured into ice-water, and the crystals are filtered off with suction and dried in a vacuum desiccator.
Yield: 9.5 g (97% of theory)
200 MHz 1H-NMR (d6-DMSO): 1.32, t, 3H; 2.63, s, 3H; 2.73, s, 3H; 4.13, q, 2H; 7.15, d, 1H; 7.77, m, 2H; 12.5, s, 1H;

At 0xc2x0 C., 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred overnight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a colourless foam.
200 MHz 1H-NMR (CDCl3): 1.03, t, 3H; 1.61, t, 2H; 1.92, hex, 2H; 2.67, s, 3H; 3.10, t, 2H; 4.42, quart., 2H; 7.27, t, 1H; 8.20, dd, 1H; 8.67, d, 1H; 10.18, s, 1H.

At 0xc2x0 C., 2.80 g (8.6 mmol) of 2-(2-propoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are added slowly to 5.13 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 3.50 g (96%) of a colourless foam. Rf=0.49 (dichloromethane/methanol=95:5)
200 MHz 1H-NMR (CDCl3): 1.03, 2t, 6H; 1.95, m, 4H; 2.81, s, 3H; 3.22, t, 2H; 4.11, t., 2H; 7.09, m, 1H; 8.06, dd, 1H; 8.21 m, 1H; 12.0, s, 1H.

At 0xc2x0 C., 0.31 g (0.9 mmol) of 2-(2-ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one are added slowly to 0.54 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 0.355 g (89%) of a colourless foam. Rf=0.50 (dichloromethane/methanol=20:1)
200 MHz 1H-NMR (CDCl3): 1.05, t, 3H; 1.66, t, 3H; 1.95, m, 2H; 2.61, s, 3H, 3.11, t, 2H; 4.15, s, 3H; 4.40, quart., 2H; 6.65, s, 1H, 8.72, s, 1H; 9.75, s, 1H.

At 0xc2x0 C., 1.70 g (5.21 mmol) of 2-(2-ethoxy-phenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are added slowly to 3.12 ml of chlorosulphonic acid. The reaction mixture is stirred at room temperature overnight and then poured into ice-water and extracted with dichloromethane. This gives 2.10 g (94%) of a colourless foam.
400 MHz 1H-NMR (CDCl3): 1.03, t, 3H; 1.35, t, 3H; 1.62, t, 3H; 1.92, sex., 2H; 3.07, quart., 2H; 3.12, t, 2H; 4.42, quart., 2H; 7.38, d, 1H; 8.19, dd, 1H; 8.70, d, 1H; 10.08, s, broad, 1H.

2.11 g (528 mmol) of 60% strength sodium hydride are initially charged in 50 ml of absolute tetrahydrofuran, and 15.7 g (52.8 mmol) of diethyl methanediphosphonate are added dropwise. The mixture is stirred at room temperature for another 30 minutes, and 10.1 g (52.8 mmol) of 1-benzyl-4-piperidone are then added. The mixture is stirred for one hour at room temperature and for one hour under reflux, concentrated, admixed with water and extracted three times with dichloromethane, and the organic phases are dried over sodium sulphate and concentrated. The residue is hydrogenated in 50 ml of ethanol over 1.7 g 10% palladium-carbon at room temperature and 3 bar. The catalyst is filtered off with suction and the filtrate is concentrated.
Yield: 12.5 g (100% of theory)
400 MHz, 1H-NMR (CDCl3): 1.13, m, 2H; 1.32, t, 6H; 1.69, dd, 2H; 1.74-1.95, m, 4H; 2.62, dt, 2H; 3.05, m, 2H; 4.1, m, 4H.

40 g (571 mmol) of crotonaldehyde are dissolved in 80 ml of acetic acid and, at 0xc2x0 C., admixed dropwise with a solution of 137 g (1.99 mol) of sodium nitrite in 300 ml of water. The mixture is stirred at room temperature for 2 hours, diluted with 800 ml of water and extracted 3 times with dichloromethane. The organic phase is dried, and chromatography (cyclohexane/ethyl acetate) gives 13.8 g (18.9%) of 5-methyl-4-furoxanecarbaldehyde.
200 MHz 1H-NMR (CDCl3):2.39, s, 3H; 10.10, s, 1H.

13.5 g (105 mmol) of 5-methyl-4-furoxanecarbaldehyde are dissolved in 200 ml of acetone and, at 0xc2x0 C., admixed dropwise with a solution of 16.86 g (168 mmol) of chromium trioxide in 120 ml of a 2.2M sulphuric acid. The mixture is stirred at 10-15xc2x0 C. for 2 hours and then at room temperature overnight. With cooling, 100 ml of isopropanol are added dropwise and, after 30 minutes, the solvent is removed under reduced pressure. The aqueous phase is extracted 3 times with ether, the organic phase is dried over magnesium sulphate and the solvent is removed under reduced pressure. The residue is dissolved in 1M sodium hydroxide solution and the solution is extracted 3 times with ether. The aqueous phase is acidified and extracted 3 times with ether. The organic phase is dried and the solvent is removed under reduced pressure. The residue is stirred with petroleum ether and filtered off with suction.
6.92 g of the residue are refluxed with 10 ml of thionyl chloride in 20 ml of dichloromethane for 6 hours. The mixture is diluted with toluene, filtered and concentrated using a rotary evaporator. The residue is once more taken up in dichloromethane, admixed with 10 ml of thionyl chloride and refluxed for 48 hours. The solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 2.00 g (25%) of colourless crystals.
200 MHz 1H-NMR (CDCl3): 241, s.

2.75 g (14.7 mmol) of Boc-piperazine and 1.49 g of triethylamine are dissolved in 20 ml of dichloromethane and, at 0xc2x0 C., admixed a little at a time with 2.00 g (12.3 mmol) of 5-methyl-4-furoxanecarbonyl chloride. The mixture is stirred for 30 minutes at 0xc2x0 C. and for 2 hours at room temperature, diluted with dichloromethane and washed with water. The solvent is removed under reduced pressure and the residue is purified by chromatography (cyclohexane/ethyl acetate). This gives 3.33 g (87%) of 1-(5-methyl-4-furoxanecarbonyl)-4-tert-butyl-oxycarbonyl-piperazine.
200 MHz 1H-NMR (CDCl3): 1.50, s, 9H; 2.30, s, 3H; 3.55, m, 4H; 3.78, m, 2H; 3.87, m, 2H.

3.12 g (10 mmol) of 1-(5-methyl-4-furoxanecarbonyl)-4-tert-butyl-oxycarbonyl-piperazine are dissolved in 20 ml of dichloromethane and, at 0xc2x0 C., admixed with 2 ml of trifluoroacetic acid. The mixture is allowed to warm to room temperature and stirred for 72 hours. After addition of 10 ml of ether, the precipitate is filtered off with suction and dried. This gives 2.47 g (83%) of 1-(5-methyl-4-furoxanecarbonyl)-piperazine trifluoroacetate.
200 MHz 1H-NMR (DMSO-d6): 2.18, s, 3H; 3.18, m, 2H; 3.25, m, 2H; 3.83, m, 2H; 3.90, m, 2H; 8.89, s, broad, 2H.